Presentation on theme: "Pharmaceutical Development"— Presentation transcript:
1 Pharmaceutical Development Lynda PaleshnuikTraining workshop: Training workshop on regulatory requirements for registration of Artemisinin based combined medicines and assessment of data submitted to regulatory authorities, February 23-27, 2009, Kampala, Uganda.
2 Acronyms ACT – artemisinin-based combination therapy API – active pharmaceutical ingredientBCS – biopharmaceutics classification systemBE – bioequivalenceCTD – common technical documentFDC – fixed dose combinationFPP – finished pharmaceutical product
3 Pharmaceutical Development Overview Important Background Information- ACT’s in the Expression of Interest (EOI)/Comparators- The Role of BE in Quality Assessment- Requirements for “Established” Generic Products- WHO Guidelines for Pharmaceutical Development
4 Pharmaceutical Development Overview DefinitionsFormulation DevelopmentApproaches: Empirical vs SystematicReverse-engineeringAPI CharacteristicsAPI-API and API-Excipient CompatibilityExcipient choices: function and concentration
5 Pharmaceutical Development Overview FPP Development DataDissolutionScoring RequirementsJustification of OveragesMicrobial AttributesCompatibility with Reconstitution Diluents/Dosage DevicesComparative Formulation Tables
6 Pharmaceutical Development Overview Process DevelopmentSummaries/Conclusions of Developmental Work
7 Expression of Interest (EOI) The current EOI (6th) covers 7 API’s in 4 combination products:Artemether/Lumefantrine FDCArtesunate/Amodiaquine FDC or co-blisteredArtesunate/Mefloquine FDC or co-blisteredArtesunate/Sulfadoxine/Pyrimethamine FDC or co-blistered
8 ComparatorsThe current comparator list (October 2008) lists comparators for each of the ACT’s:Artemether/Lumefantrine: Riamet or CoartemArtesunate/Amodiaquine: Arsuamoon and FlavoquineArtesunate/Mefloquine: Arsuamoon and LariamArtesunate/Sulfadoxine/Pyrimethamine: Arsuamoon and Fansidar
9 The Role of BE in Quality Assessment Comparator products are available for each of the ACT’s, therefore a biostudy should be provided for each dossier.In exceptional cases, (eg proportional strengths of a prequalified product), a biowaiver may be acceptable. BCS-based biowaivers are not appropriate for ACT’s.In either case, biostudy or biowaiver, a biobatch is used to demonstrate bioequivalence or similarity to the comparator.This biobatch is the cornerstone of the quality assessment process.Biobatch: the test batch used in the biostudy to demonstrate bioequivalence, or used in the biowaiver to demonstrate similarity, compared to the comparator product.
10 The Role of BE in Quality Assessment Along with pharmaceutical development data, the biobatch represents key information that is used throughout the quality assessment.The manufacturer must be careful to develop a production batch which is representative of the biobatch.The quality assessor must confirm during assessment that the proposed production batches are representative of the biobatch.To be considered representative of the biobatch, production batches must have the same formulation and manufacturing process (equipment, process and controls) as the biobatch.
11 Requirements for New Versus Established Generics Definition: Established Generic ProductA product which has been on the market for at least 5 yearsANDat least 10 batches were manufactured in the previous year.
12 Requirements for New Versus Established Generics Established Generic Requirements:1) Pharmaceutical development report if available.2) Annual report for the previous year.Annual report = annual quality review or annual product review (APR)The annual report requirement fills the requirement for P.3.5 (3.2) Process Validation (protocol/report), and for P.2 (3.7) sections regarding pharmaceutical development data.
13 Annual Report Requirements Objective: verifying the consistency of the quality of the FPP and its manufacturing processRequirements:Review conducted on NLT 10 consecutive production batches manufactured over the previous year.Rejected batches should not be included in the analysis but must be reported separately together with the reports of failure investigationsAll data from batches manufactured during the review period must be included in the review.Data should be presented in tabular form or in graphical form (i.e., charts or graphs), when applicable.
14 Annual Report Requirements The annual report should include:A review of starting and primary packing materials used in the FPP, especially those from new sources.A tabulated review and statistical analysis of quality control and in-process control results.A review of all batches that failed to meet established specification(s).A review of all critical deviations or non-conformances and related investigations.A review of all changes carried out to the processes or analytical methods.A review of the results of the stability-monitoring program.A review of all quality-related returns, complaints and recalls, including export only medicinal products.A review of adequacy of previous corrective actions.A list of validated analytical and manufacturing procedures and their revalidation dates.
15 Pharmaceutical Development WHO Guidelines Guideline on Submission of Documentation for Prequalification of Multi-source (Generic) Finished Pharmaceutical Products (FPPs) Used in the Treatment of HIV/AIDS, Malaria and TuberculosisQAS/ January 2008 – Draft Pharmaceutical Development for Multisource (Generic) Pharmaceutical Products p/PharmDevelGener_QAS08_251_ pdf
16 Pharmaceutical Development WHO Guidelines TRS 929 Annex 5: Guidelines for Registration of fixed-dose combination medicinal products.Key sections:6.3 Quality6.3.2 Development considerations for FDC’s.Appendix 3: pharmaceutical development (or preformulation) studies.Supplement 2 to the Generics Main Guide.
17 Pharmaceutical Development Guidelines ICH Q8R1 dated November 13, 2008CDER Q8R1Gives clarification of ICHQ8 conceptsDescribes the principles of QbD (quality by design)Shows how key concepts and tools such as design space can be put into practice.
18 Definitions Critical quality attributes (CQA’s): Physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality. CQAs are generally associated with the API(s), excipients, intermediates, and drug product.CQAs include the properties that impart the desired quality, safety, and efficacy. CQAs of solid oral dosage forms are typically those aspects affecting product purity, potency, stability, and drug release.
19 Definitions Critical quality attributes (CQA’s): [continued] For APIs or intermediates, the CQAs can additionally include those properties (e.g., particle size distribution, bulk density) that affect downstream processability.Drug product CQAs are used to guide the product and process development. Potential drug product CQAs can be identified from the target product profile and/or prior knowledge. The list of potential CQAs can be modified when the formulation and manufacturing process are selected and as product knowledge and process understanding increase. Quality risk management can be used to prioritize the list of potential CQAs for subsequent evaluation.
20 Definitions Critical Process Parameters (CPPs): A process parameter whose variability has an impact on a CQA and therefore should be monitored or controlled to ensure the process produces the desired quality.
21 Definitions Target product profile: A prospective and dynamic summary of the quality characteristics of a drug product that ideally will be achieved to ensure that the desired quality, and hence the safety and efficacy, of a drug product is realised. The target product profile forms the basis of design for the development of the product.Considerations should include dosage form and route, strengths, API release or delivery and PK considerations (eg delayed vs immediate vs controlled release) appropriate to the dosage form, and quality criteria (eg sterility, purity) appropriate for the intended marketed product.
22 Pharmaceutical Development Definition/Purpose The information and knowledge gained from pharmaceutical development studies and experience with the manufacture of primary batches provide scientific understanding to support the proposed CQAs of the FPP (quality control (QC) and in-process control (IPC) acceptance limits) and CPPs and their manufacturing controls, which can be essential inputs for quality risk management. [Draft QAS ]
23 Pharmaceutical Development Definition/Purpose Studies conducted to establish that the dosage form, formulation, manufacturing process, container closure system, microbiological attributes and usage instructions are appropriate for the specified purpose.Studies should identify formulation and process attributes (critical parameters) that can influence batch reproducibility, product performance and FPP quality, including stability.[Generics Main Guideline]
24 Pharmaceutical Equivalence Definition Products are pharmaceutical equivalents if they contain the same molar amount of the same API(s) in the same dosage form, if they meet comparable standards, and if they are intended to be administered by the same route. Pharmaceutical equivalence does not necessarily imply therapeutic equivalence, as differences in the excipients and/or the manufacturing process and some other variables can lead to differences in product performance.i.e: same amount of same API in the same dosage form with the same route of administration. Excipients may differ.Therapeutic Equivalence is demonstrated by BE studies.Ref: TRS 937 Annex 7: Guidelines on Registration Requirements to Establish Interchangeability
25 Approaches to Pharmaceutical Development: Empirical vs Systematic
26 Empirical vs Systematic Empirical (traditional): relies on experience and observation, rather than theory and systemsSystematic: exemplified by QbD (quality by design)This talk deals with new generic drugs, solid orals, and development via the empirical approach.
27 Formulation Development: Reverse Engineering Reverse Engineering: formulating a drug based on the qualitative and quantitative (Q&Q) formulation of the comparator drug.Note that reverse engineering is not practical when there is more than one comparator for a single FPP-FDC.Example: an artesunate/amodioquine FDC is unlikely to be made Q&Q to Arsuamoon Tablets plus Flavoquine Tablets.Reverse engineering can be a starting point. However, the establishment of bioequivalence between the finished product and the comparator is the definitive measure of product equivalence.
28 Formulation Development API Characteristics SolubilityLow solubility API (all ACT API’s with the exception of amodioquine HCl):- Particle size distribution and polymorphism are important.- Particle size distribution and polymorphic form in the final product should be the same as the lot used in biostudies.
31 Formulation Development API Characteristics Stability – intrinsic stability of API, compatibility studiesHygroscopicity –in relation to the manufacturing process and final FPPFlowabilityReference to peer-reviewed literature is accepted.
32 Formulation Development Compatibility Studies API-excipient compatibility: note that if an excipient is in the comparator, the compatibility of that excipient may be considered established. The applicant should therefore include in the dossier the qualitative composition of the comparator product(s).For FDC’s, API-API compatibility must be established.Guidance is provided in TRS 929 appendix 3 Table A.1 (2005) and Supplement 2 (2006).
33 Formulation Development Compatibility Studies: TRS 929
34 Formulation Development Compatibility Studies: S2 Provides a table of possible conditions for stress testing the dose-proportional mixture of the APIs in solution or suspension, and in solid state.Provides a format for reporting of results.Note: A visual description is not adequate, reporting should include chromatographic results (purity/potency).
35 Formulation Development Excipient Choices The function and concentration of excipients should be discussed.Where a functional excipient is used, eg pH-adjusting agents, buffers, stabilizers (eg antioxidants and chelating agents), preservatives and dissolution modifiers (eg surface active agents), their ability to perform throughout the shelf-life should be demonstrated.
36 Formulation Development Excipient Choices Some excipients are multi-functional by nature; different grades of the same excipients (ie those with different physical properties) may have different functional characteristics.In these cases, the pharmacopeial specifications may not be sufficient, and user requirements may be additionally required.See Annex 5 in QAS , “Usual range of excipients in Tablets and Capsules”. This table presents common excipients with their various uses (eg MCC as binder, diluent or disintegrant) and the usual concentration.
38 Formulation Development Excipient Choices Additional sources of informationFDA Inactive ingredients database:Eg. pregelatinized starch:Entries for starch 1500 pregelatinized, starch pregelatinized, starch pregelatinized corn, and starch pregelatinized tapiocaHealth Canada inactive ingredients site:imn_list1_e.html
39 Formulation Development Excipient Choices NOTE: clearly identify all excipients in the formulation, including grade used, in the executed biobatch records and the blank production records.
40 FPP Development Data Dissolution A discriminating dissolution method should be developed for the final composition of the FPP.Limits should be set for each API in fixed-dose FPPs.The dissolution method should be incorporated into the stability and quality control programs.Multipoint dissolution profiles of both the test and the reference FPPs should be compared.
41 FPP Development Data Dissolution For highly soluble and rapidly dissolving drug products (BCS class 1 and 3), a single-point dissolution test limit of NLT 85% (80% Q) in 30 minutes or less is sufficient.For slowly dissolving or poorly water soluble drugs (BCS class 2 and 4), a two-point dissolution range is recommended, for example one point at 15 minutes and the other after 85% dissolution (eg 30, 45 or 60 minutes).For FDC’s (TRS 929), “Multipoint limits should normally be established for routine quality control of each active.”
42 FPP Development Data Scoring Requirements The EOI states: “The appropriate solid dosage formulations, which are scored for flexible dosing purposes, should be supported by relevant evidence on equal distribution of active ingredients in the scored products, especially in the case of FDC’s.”Supporting data should include content uniformity (CU) of tablet halves. If weight uniformity is acceptable in FPP specifications, it is acceptable for uniformity of tablet halves.CU requirements: as specified in the WHO FDC guideline, whenever ANY API in an FDC is < 25 mg or 25% of the tablet weight, ALL API’s are subject to content uniformity requirements.
43 FPP Development Data Scoring Requirements Establishing content uniformity of tablet halves is a one- time study which should be presented with pharmaceutical development data, and should include:- a divisibility study in accordance with USP General Chapter <905>, conducted on individual tablet halves.- reporting of individual values of tablet halves as well as the RSD.
44 FPP Development Data Overages Justification of Overages:An overage is only possible for API’s.The only acceptable justification is loss during manufacture.This can be demonstrated by product release results (potency) that show that the overage has not survived the manufacturing process, ie assay results close to 100%.
45 FPP Development Data Microbial Attributes Microbiological attributes of the FPP should be discussed, including:- the rationale for not performing microbial limits testing for non- sterile products- the selection and effectiveness of preservative systems in products containing antimicrobial preservatives.- antimicrobial effectiveness of products that are inherently antimicrobialFor sterile products, the integrity of the container closure system to prevent microbial contamination should be addressed.
46 FPP Development Data Microbial Attributes Selection and effectiveness of preservatives:The formulation should include the minimum concentration of preservative that gives the required level of efficacy through the shelf-life.To this end, the drug product should be formulated with different concentrations of preservatives and a microbial challenge test on each of the formulations conducted to determine the “least necessary” but still effective concentration.The microbial challenge test should be performed to establish and justify the amount of the antimicrobial preservatives to be used.
47 FPP Development Data Microbial Attributes Wherever relevant, microbial challenge testing under test conditions that simulate patient use (as far as possible) should be performed and documented during development.
48 FPP Development Data FPP Compatibility Studies Section i) of the Generics Main Guide, and Section P.2.6 of the CTD.Compatibility with Reconstitution Diluents/Dosage DevicesThis is often erroneously filled in with API-excipient and API-API compatibility studies. The latter are included in P (CTD) or a) and c) (Generics Main Guide).Data included in this section should only be on compatibility studies with reconstitution diluents and/or dosage devices to support claims in the label.
49 FPP Development Data Comparative Formulation Tables
50 Process DevelopmentThe selection and optimization of the manufacturing process, in particular its critical aspects, should be explained and documented.Where relevant, the method of sterilization should be explained and justified.The progress from preformulation to formulation to pilot to production scale batches (approved batch size) should be shown to be logical, reasoned and continuous.
51 Process Development Common deficiencies: Critical manufacturing steps were not identifiedFailure to fully characterize key operating parameters of the process, for example granulation end-point.Failure to justify elements of the process, for example why direct compression is chosen for one layer of a bilayer tablet, why extra- granular disintegrants are added.In-process tests to control the process were not discussed.
52 Pharmaceutical Development Reports Summaries/Conclusions Capturing Key DataWhen presenting formulation/process development data, begin with the end in mind: what conclusions can be drawn from the data?Large amounts of data on pilot formulations, scale-up etc, without summarizing key information, are not constructive.
53 Pharmaceutical Development Reports Summaries/Conclusions Capturing Key DataKey information to capture in summaries:1) Formulation development gives information on critical quality attributes: which excipients are critical to product performance/quality attributes (CQA).Example: if formulation studies indicated that a particular exicient, excipient grade or excipient amount was required to obtain acceptable dissolution, this is a CQA.
54 Pharmaceutical Development Reports Summaries/Conclusions 2) Changes in process during development give information on critical process parameters (CPP):Example: if process development studies indicated that particular parameter(s) (eg blend speed and time, granulation end-point) were necessary to obtain a product with the required quality characteristics, these are CPPs.
55 Summary/Conclusions of Development Data Including the summaries/conclusions in the previous slide in the dossier will expedite the quality assessment.The conclusions of pharmaceutical development should be observed in:1) executed biobatch records2) blank master production records.For manufacturers: information on CQA’s and CPP’s should be reflected in the proposed formulation, manufacturing process and controls in the master production documents and executed biobatch records. These must be submitted in the dossier.
56 Summary/Conclusions of Development Data For assessors: There are two main considerations when assessing master production documents:1) information on CQAs and CPPs determined during pharmaceutical development should be reflected in master batch records.2) Master batch records must reflect the formulation/process/ controls of the biobatch.Formulation/process development leads to the batch used in biostudies, which must be representative of the production batches and reflected in master batch records.